Schnyder crystalline corneal dystrophy (SCCD, OMIM 121800) is a rare inherited disorder for which the most prominent feature is progressive, bilateral corneal clouding in the eyes of affected individuals. Although this can appear as early as the first decade of life, it more commonly occurs in the late teens. Thereafter, the clinical course is somewhat variable, although reduced vision (particularly under brightly lit conditions) usually mandates intervention in the fourth or fifth decades of life. Phototherapeutic keratectomy (a procedure similar to that used in laser vision correction) can be temporarily useful in selected cases, but the definitive treatment is corneal transplantation. SCCD affects both sexes equally, and is found in multiple ethnic groups around the globe.
Pathophysiologically, SCCD appears to result from an abnormality in lipid metabolism in the cells of the cornea, and perhaps elsewhere in the body. Pathologic examination of corneal tissue removed from affected patients during transplantation surgery has revealed a tenfold increase in local cholesterol levels, and a fivefold increase in phospholipids. Immunohistochemical analysis of the same tissue is consistent with an underlying defect in HDL metabolism. SCCD has also been linked to increased serum cholesterol and thus, to an elevated risk of cardiovascular events such as myocardial infarction (heart attack) and stroke.
Although SCCD appears strongly genetic, identification of a causal gene has been elusive. Shearman et al. performed linkage analysis on a large family originally of Swedish/Finnish ancestry, localizing the defective gene to the short arm of chromosome 1, at 1p34-36 (Hum Mol Genet 5:1667-1672 (1996)). Theendakara et al. further narrowed the SCCD locus, reducing the candidate region to a 1.58 Mbp (million base pair) interval lying between genetic markers D1S244 and D1S3153 (Hum Genet 114:594-600 (2004)). Recently, Aldave et al. sequenced 15 of the 31 positional candidate genes within this region, finding no pathogenic mutations and tentatively excluding them as causing SCCD (Mol Vis 11:713-716 (2005)).
According to the NCBI genome database, UBIAD1 encodes a protein of 338 amino acids. UBIAD1 is a highly conserved gene, almost 100% identical across much of its length in vertebrate genomes and with extensive homology in insects. InterPro, Pfam and ProSite predict that UBIAD1 contains a prenyltransferase domain from residues 58-333, for which the archetype is bacterial protein UbiA. PSORTII predicts 7 transmembrane domains and integral membrane localization. Multiple transmembrane helices are also predicted by HMMTOP, TMPRED, TOPPRED and TMM. No signal peptide or cleavage signal is predicted by SignalP. The probability of mitochondrial targetting is unlikely (0.14) according to MITOPROT. The protein is not predicted to have a peroxisomal targeting signal 1 motif by PTS1. No potential GPI-modification site was predicted by bigPI or DGPI. No myristoylation site was predicted by NMT. No PEST domains were predicted by PESTfind. No prenylation sites were predicted by PrePS.
UBIAD1 is ubiquitously expressed; however the eye has been identified to have the highest normalized expression distribution of the 39 tissues reported at the Source (//genome-www5.Stanford) and of the 49 tissues identified at the Expression Profile Viewer (//www.ncbi.nlm/nih.gov).
McGarvey et al. reported two UBIAD1 transcripts of ˜1.5 and ˜3.5 kb (Oncogene 20:1042-1051 (2001)). The 1.5 kb transcript is attributable to the 1520 bp UBIAD1 reference sequence in NCBI (NM-013319.1) and Ensembl (Build 38) coding for a 338 amino acid protein. The 3.5 kb transcript identified by McGarvey et al. corresponds to the Ensembl (Build 38) gene predictions 3646 bp ENST00000376810. Also identified is a 3140 bp Ensembl (Build 38) gene predictions ENST00000240179 and NCBI cDNA clone AK074890. There is a rare variant that is predicted to splice out the UBIAD1 second exon and add three additional amino acids to the 3′end of exon 1 (Ensembl ENST00000376804; Expasy Q9Y5Z9-2). These additional 3 amino acids are derived from a putative ubiquitin-conjugating enzyme E2 variant 2 (UBE2V2) pseudogene that is approximately 8.6 kb from the 3′ UBIAD1 second exon (NCBI Accession AL031291).